Homocysteine-induced oxidative stress through TLR4/NF-κB/DNMT1-mediated LOX-1 DNA methylation in endothelial cells

Abstract

Atherosclerosis (AS) is a progressive disease of multifactorial origin, which occurs in response to endothelial injury. Increased homocysteine (Hcy) is considered a major cause of endothelial dysfunction, oxidative stress and DNA methylation; however, the mechanisms remain to be fully elucidated. The aim of the present study was to investigate whether Hcy causes injury to endothelial cells (ECs) by the effect of lectin‑like oxidized‑low density lipoprotein receptor‑1 (LOX‑1) DNA methylation through toll‑like receptor 4(TLR4)/nuclear factor (NF)‑κB/DNA methyltransferase (DNMT)1. The ECs were treated with different concentrations of Hcy, and it was found that Hcy promoted the expression of TLR4, leading to EC injury. The effect of oxidative stress was analyzed by measuring superoxide dismutase, malondialdehyde and hydrogen peroxide in the ECs. In addition, the association between NF‑κB and DNMT1 was examined by treatment of the ECs with pyrrolidine dithiocarbamate (PDTC). The results suggested that Hcy induced LOX‑1 DNA hypomethyaltion to promote the expression levels of LOX‑1. Taken together, Hcy injured the ECs through the effect of methylation and trans‑sulfuration metabolism of LOX‑1 through TLR4/NF‑κB/DNMT1. Following injury to the ECs, lipids, particularly ox‑LDL, accumulated in the sub‑endothelial layer to promote the formation of AS.

Associations of the MTHFR rs1801133 polymorphism with coronary artery disease and lipid levels: a systematic review and updated meta-analysis

“…In the T allele carriers of the rs1801133 polymorphism, the function of MTHFR may be affected since the normal alanine residue is replaced by a valine residue in the polypeptide, which in turn affects the production of 5-MTHF and the remethylation of homcysteine, resulting in elevated plasma homosysteine levels. Studies have shown that homocysteine is a risk factor for CAD, and oxidative stress [ 33 ], vascular inflammation [ 34 ] and endothelial injury [ 35 ] are involved in the underlying mechanisms in which homocysteine causes CAD. All these events are likely to trigger the development of atherosclerosis and arterial thrombosis.…”

Emodin Rescued Hyperhomocysteinemia-Induced Dementia and Alzheimer’s Disease-Like Features in Rats

“…A previous study showed the increased DNA methylation with increased DNMT1 and DNMT3α protein levels in HHcy mice brain (Kalani et al, 2014). However, HHcy was also associated with the downregulated DNMTs both in vitro (Lin et al, 2014; Ma et al, 2017) and in vivo (Fuso et al, 2011; Li et al, 2017). Diet and genetically induced HHcy in 3×Tg AD mice resulted a significant increase of the S-adenosylhomocysteine/S-adenosylmethionine ratio, reduced DNMTs (DNMT1, DNMT3α, and DNMT3β), and hypomethylation of 5-LO DNA in the brain cortex homogenates (Li et al, 2017).…”

Targeting LOX‐1 in atherosclerosis and vasculopathy: current knowledge and future perspectives

“…The phosphorylation of p66 shc is increased in ECs exposed to ox‐LDL, and this effect is blocked by treatment with LOX‐1 siRNA . Interestingly, LOX‐1 DNA hypomethylation and gene upregulation induced by homocysteine regulates oxidative stress . Mitochondrial DNA (mtDNA) is very sensitive to oxidative stress.…”